Von Willebrand factor protects against acute CCl4-induced hepatotoxicity through phospho-p38 MAPK signaling pathway inhibition
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The blood glycoprotein von Willebrand factor (vWF) is involved in coagulopathy and inflammation; however, its role in the pathogenesis of acute liver failure, as suggested by its higher expression levels in such patients, remains unknown. In this study, vWF-knockout (KO) mice showed more severe carbon tetrachloride (CCl4)-induced liver injury than wild-type mice. Patients with acute liver injury also showed elevated vWF protein activity and expression in liver tissues, as compared to healthy individuals. Using the mouse model and cultured human umbilical vein endothelial cells (HUVECs), CCl4 was found to directly increase vWF protein expression through interaction with the highly expressed vWF receptor, GPIbα. Microarray analysis revealed that the genes showing the most differential expression in response to CCl4-induced liver injury and vWF deficiency were related to the MAPK signaling pathway. Subsequent inhibition of vWF protein activity in HUVECs led to activation of the MAPK signal pathway and elevated production of FGL2, and treatment with a phospho-p38 inhibitor suppressed the CCl4-induced production of FGL2. Exposure of liver sinusoidal endothelial cells isolated from the vWF-KO acute liver injury model mice to phospho-p38 inhibitor also decreased FGL2 expression. The vWF/GPIbα axis plays a protective role against development of acute liver injury by attenuating FGL2 production through the MAPK signaling pathway. Collectively, these data provide insight into the pathogenesis of acute liver injury and a potential novel strategy for its treatment.
Keywordsvon Willebrand Factor Acute liver injury Carbon tetrachloride Fibrinogen-like protein 2
We would like to thank Chen-hui Wang for isolating the LSECs from mice and Xiao-he Shen for technical assistance in the Ets-1 siRNA transduction investigations.
This research was supported by grants from the National Natural Science Foundation of China (no. 31500710 and no. 31500720) and the National Key Research and Development Project (2016YFA0502204).
XY and YZW conceived of and designed the study; HJS, JC, and HZ carried out the experiments; YL collected the specimens from patients and healthy donors; XY, HJS, JC, HZ, and BN analyzed and interpreted the data; JCvV made critical revision to the article for important intellectual content. All authors made substantial contributions towards drafting the manuscript, reviewing the final manuscript for intellectual content, and authorizing the submission.
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Conflict of interests
The authors declare that they have no conflict of interest.
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